Alzheimer's disease is characterized by the accumulation and deposition of A[unreadable] peptides within the brain, leading to perturbation in synaptic function and neuronal loss that underlies the loss of cognition that typifies the disease. A[unreadable] can be cleared from the brain by proteinases, acting both intracellularly and extracellularly, as well as the efflux of A[unreadable] into the peripheral circulation. Thus, therapeutic strategies that facilitate A[unreadable] clearance are of particular interest and importance. [unreadable] [unreadable] Genetic analysis of familial forms of AD has established the centrality of APP processing and A[unreadable] production to disease pathogenesis. An isoform of Apolipoprotein E (apoE4) has been shown to confer dramatically increased risk for late onset AD, however, the mechanisms subserving this effect are unclear. ApoE is the principal apolipoprotein in the brain and is secreted from astrocytes within a nascent high density lipoprotein (HDL)-like particle that is assembled by the addition of lipids to ApoE, which acts to scaffold HDL formation. The lipidation of ApoE is carried out by the action of the ABC transporter ABCA1 that transfers both phospholipids and cholesterol to ApoE. Importantly, ApoE binds avidly to A[unreadable] peptides, and lipidated forms of ApoE exhibit a greater capacity to interact with A[unreadable] compared to unlipidated ApoE. Importantly, the degree of ApoE lipidation governs whether its interaction with A[unreadable] leads to clearance of the peptides from the brain, or alternatively to form fibrils and be deposited into plaques. There is now compelling experimental evidence that ApoE lipidation favors the clearance of A[unreadable] peptides from the brain. It follows that therapeutic agents that increase the abundance of highly lipidated forms of ApoE may be of utility in attenuating disease pathogenesis. [unreadable] [unreadable] The expression of both ApoE and ABCA1 are coordinately regulated by the type II nuclear receptor, liver X receptor (LXR). LXRs are ligand activated transcription factors which bind to the promoters of these (and other genes of lipid metabolism) and when activated stimulate an increase in the levels of lipidated forms of ApoE. We report that treatment of 1 year old hAPP-expressing Tg2576 mice with the LXR agonist GW3965 results in a significant (>50%) reduction in A[unreadable] peptide levels and plaque load. We postulate that this effect is due to the enhanced ability to proteolytically clear A[unreadable] peptides from the brain. We propose to i). to establish the therapeutic conditions required to prevent and reverse the development of AD-related pathology in an animal model of AD, ii). to definitively establish the role of LXRs in A[unreadable] metabolism by examination of murine models of AD lacking LXRa and LXR[unreadable], validating these receptors as therapeutic targets in AD, and iii). to ascertain the molecular mechanisms through which the LXR agonists facilitate the proteolytic degradation of A[unreadable] peptides. [unreadable] [unreadable] [unreadable]